Researchers have uncovered mutations in the phosphatase Wip1 that enable cancer cells to foil the tumor suppressor p53, according to a study in The Journal of Cell Biology. The results could provide a new target for the treatment of certain cancers.
Like a battlefield surgeon who has to decide which casualties can be saved, p53 performs triage on cells with injured DNA. If the damage is serious, p53 spurs the cells to die or stop proliferating. But after milder hits, p53 activates a DNA damage response (DDR) mechanism, which instigates repairs, and temporarily prevent cells from advancing any farther in the cell cycle. Once cells have mended their DNA, the phosphatase Wip1 enables them to re-enter the cell cycle by shutting down p53 and DDR proteins. Because p53 and the DDR stymie cancer cells, it's no surprise that the rogue cells find ways to circumvent this protection. More than half of all cancers accrue mutations in the p53 gene, for example. Now, researchers from the Czech Republic and the Netherlands tested whether some cells instead carry mutations in the PPM1D gene, which encodes Wip1, to shut down p53.
The team analyzed human tumor cell lines that harbor functional p53. Two of the lines displayed mutations in exon 6 of the PPM1D gene that resulted in a shortened version of Wip1. The truncated Wip1 was more stable than the full-length version of the protein, allowing cells to switch off p53 and continue the cell cycle in the presence of DNA damage. Depleting the truncated Wip1, however, halted the cell cycle until the DNA was repaired.
The researchers then looked for PPM1D mutations in 1,000 patients who had colorectal or breast and ovarian cancer. Four of the patients carried mutations, whereas none of the 450 cancer-free individuals did. All of these DNA alterations fell in exon 6 and caused production of shortened Wip1. To the researchers' surprise, the mutations occurred in the cancer patients' non-tumor cells as well. That suggests that the patients were born with PPM1D mutations, which set them up for cancer later in life but apparently caused no other illnesses.
"We've identified a new mechanism that could lead to inactivation of p53 in cells and inactivation of the DNA damage response," says senior author Libor Macurek. The team suspects that PPM1D mutations could turn up in a variety of tumors. If so, targeting the short but overactive form of Wip1 could provide a new way to treat these cancers.
Kleiblova, P., et al. 2013. J. Cell Biol. doi:10.1083/jcb.201210031
Rockefeller University Press: http://www.rupress.org/
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
Doctors have used perfect replicas of childrens' hearts to uncover and repair hidden defects
An experiment testing people’s altruism in the face of electric shocks is clear on one thing: we are drawn to these little blasts
Researchers gear up tests in West Africa to see whether blood from Ebola survivors can help people who are sick with the disease. This is part of a broader effort to test therapies in West Africa.
The virus's foray into Europe coincides with peak production of Christmas turkeys, the poultry species most vulnerable to bird flu
A novel kind of nanoparticle could lead to more effective cancer treatments.Patients and doctors often don’t know if surgery to remove cancerous tissue was successful until scans are performed months later. A new kind of nanoparticle could show patients if they’re in the clear much earlier.
One challenge in evaluating the effectiveness of different medical procedures, is that patients behave differently after different procedures. Is this true for patients getting heart surgery?
It is only in the aftermath of treatment that survivors discern that their adrenalin alone wont fuel the rest of their recovery. For many, surviving cancer is followed by even more hardship
Just down the road from Facebook and Google, Dr. Phil Wagner runs a laboratory dedicated to optimizing the performance of some of the world's top athletes. At Sparta Performance Science in Menlo Park, California, Wagner and his team bring the spirit of Silicon Valley to bear on the athletic world, helping athletes find the tiny advantages that add to championships. Join us for a trip inside the lab to see where sports meets science.
Pieter Cohen, an internist in Massachusetts, got interested in dietary supplements several years ago, when some of his …
The risk of overdiagnosis and false positives means the UK may be barking up the wrong tree in trialling a wider target age range for breast screening